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Is it time for a new diagnostic paradigm for Alzheimer disease? In a position paper published online in Lancet Neurology on July 6, a panel of experts says that when it comes to research studies, the answer is yes. Their proposal to update the current criteria, which date to 1984, is aimed at capturing the knowledge explosion that has occurred since then in understanding the biology of the disease. Combining memory testing with biomarker measurements, including genetic testing, imaging, and CSF protein assessments, the panel writes, will let researchers diagnose AD earlier and with greater accuracy. Nailing the diagnosis at the earliest possible stage with the greatest possible accuracy will be a critical factor in the success or failure of clinical trials of the many new candidate treatments coming down the pipeline.

The paper comes from first authors Bruno Dubois of the Hopital de la Salpetriere in Paris, France, and Howard Feldman of the University of British Columbia in Vancouver, Canada, who write with an additional 15 coauthors from Europe, North America, and Japan. The text presents the consensus recommendations of a working group convened in 2005 to integrate the information explosion in the field of AD biomarkers (see last year’s ARF biomarkers meeting report, for just a start), and the importance of early diagnosis, into a new framework for identifying AD.

The current criteria used to assign a diagnosis of AD were set out 23 years ago by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) working group. The other accepted criteria are those of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Both start with the finding of dementia, then go through a process of ruling out other causes to arrive at the diagnosis of AD. The clinical standard assigns a probability of AD; definitive diagnosis is only made postmortem based on brain pathology. The DSM criteria set the highest bar, requiring significant impairment in activities of daily living. The looser NINDS criteria allow an earlier diagnosis based on cognitive impairment, but neither of the currently accepted criteria captures the earliest, and presumably treatable, disease stages with high accuracy. (For more information on diagnosis, see ARF Diagnosis page).

The new approach would depend on biomarkers, not dementia, to define AD in patients with narrowly defined memory impairments. Thus, the working group recommends a core criterion of impairment in early episodic memory, bolstered by a second supporting biomarker measure. This could be medial temporal lobe atrophy, measured by MRI, abnormal levels of amyloid-β peptides or tau proteins in cerebrospinal fluid, specific patterns of brain function measured by fMRI, pathological protein deposition measured by PET, or a proven AD mutation in the family. The emphasis on biomarkers would help separate AD from look-alike diseases like frontotemporal dementias, and allow earlier diagnosis.

This approach would represent a “cultural shift” in the way AD is recognized, the authors write, “requiring more biologically focused workup than previous approaches; however, this seems to be the best way to integrate the profound advances into the clinical arena.” Rather than relying on clinical testing alone, the approach begins to define AD as a biological entity.

The devil, as always, is in the details. The recommendations are forward-looking, and much work remains to validate and implement such schemes. As yet, there are no standard procedures, no established cut-off values for normal and abnormal results for the proposed tests, the authors concede. Validation in both retrospective and prospective formats will be needed to establish working parameters. Practical issues limit much of this work to research centers, and the authors advocate an approach of adding on these new measures to ongoing studies to start to accumulate the needed validation data.

These issues are considerable, and some researchers feel it is premature to be talking about revising the diagnostic criteria based on current data. Ron Petersen of the Mayo Clinic in Rochester, Minnesota, told ARF that a meeting held in Miami last April sponsored by the Mt. Sinai Medical Center focused on the question of whether the field was ripe for a consensus conference to revise the 1984 criteria. “There were a lot of good hypotheses proposed,” said Petersen, “But we came away thinking it was too soon, and there was no consensus as to how we would go about revising the guidelines. The bottom line is that we need more longitudinal data.

“Moving to earlier diagnosis based on a single memory test and one biomarker raises the risk of misdiagnosis, and putting the label of AD on a patient has both scientific and sociological consequences,” Petersen told ARF. “We have a responsibility to our patients and the scientific community to be accurate with our labels.”

In an accompanying commentary, Norman Foster of the University of Utah in Salt Lake City writes that while the proposed criteria are not ready for clinical use, they will form a crucial framework for future discussion. He suggests that age should also be incorporated into the diagnostic scheme, since episodic memory loss in someone under 60 is far less likely to be due to AD than the same symptom in an older person.

Like the working group, Foster anticipates that great progress could be made relatively easily by incorporating the evaluation of new criteria in studies that continue to use the NINCDS-ADRDA criteria. Indeed, this kind of add-on goes on in research centers like the Mayo Clinic routinely, Petersen said.

Foster points out that before those guidelines were published, “many clinicians had previously considered [a diagnosis of AD] futile without an autopsy.” The criteria spurred research and enhanced care, but he writes that after 20-plus years, “The time is right to use the advanced technology at our disposal to improve the early, accurate diagnosis of dementia and develop more effective treatments.”—Pat McCaffrey

Comments

This position paper by Dubois et al. is a long overdue call for reassessing the criteria, assumptions, and procedures for diagnosis of Alzheimer disease. The recommendations of this work group are well reasoned and sound. However, the task of crafting “consensus” criteria will not be easy for several reasons: a) lack of a clear definition of the “disease” or clinical phenomenon; b) tremendous heterogeneity in both clinical and biological phenotypes of the “disease”; and c) lack of or poorly understood causal relationship(s) between the clinical expression of the “disease” and their biological underpinnings.

In spite of these long-standing problems the field faces, the work group has done an excellent job in laying the foundation for an ongoing effort to refine the criteria that have been used since 1984.

The authors are to be congratulated on this paper! It is very timely, the call to incorporate a biological footprint in diagnosis is appropriate, and the elimination of MCI to AD as a binary outcome is most welcome. However, from my perspective, the salient information regarding dementia diagnosis is that an individual has declined in cognitive abilities, relative to previous levels, and that the decline is sufficient to interfere with function in everyday activities. Most importantly, then, we need to know how an individual has changed relative to his/her premorbid cognitive function—this is the principle of intraindividual change. The Core Diagnostic Criterion A proposed by Dubois et al. specifies that there be objective deficit on an episodic memory measure, presumably in comparison with age- and education-matched norms. Rather than judging that individuals have declined relative to previously attained abilities, their test performances are compared with the performances of other persons. Dependence of this interindividual comparison to determine the presence of dementia is flawed on several levels: 1) it does not indicate that the individual's performance has changed from his/her prior performance; 2) it does not indicate whether the cognitive test results relate to impaired everyday function; and 3) depending on where the cutpoint is established, in a normally distributed population some percentile of nondemented individuals will be classified as "impaired." For example, if the cutpoint is 1 SD of the mean, 17 percent will be below the tail; if the cutpoint is 2 SD of the mean, 2.5 percent will be below the tail. On the other side of the coin, some clearly dementing individuals of high intellectual attainment may not be classified as impaired based on cognitive test performance because they still are able to perform at a level above the cutpoint. Moreover, there are many potential confounds (e.g., education, literacy, culture) that affect interpretation of neuropsychological test performance.

I recognize that my views about the operationalization of diagnostic criteria for MCI/AD are very much in the minority, as the diagnosis most often is on cognitive test scores. I contend, however, that this test-based approach inherently identifies some individuals as having "MCI," for example, when in fact their cognitive abilities have not changed and they continue to function normally. Depending on where the cutpoints are set and the population to which they are applied, the proportion of such non-impaired individuals in the sample will vary, contributing directly to the reported variability in the outcomes of these samples. Basing the diagnosis of impairment on the principle of intraindividual change, on the other hand, is both highly accurate and sensitive in the early detection of symptomatic AD (Storandt et al., 2006). In fact, for the subset of individuals characterized with MCI for whom underlying AD is the cause, MCI is not a risk factor for AD; it is AD in its earliest symptomatic stage. Revised criteria for AD should take into account this knowledge and discard the concept of MCI in favor of etiological diagnoses; for most cases, MCI is early-stage AD (Morris, 2006 ).